A major causes of oral cancer is the use of tobacco and alcohol. Although the etiology or oral cancer is well-known, primary prevention of oral cancer by tobacco and alcohol cessation program are only marginally effective. Since oral cancer is often preceded by the presentation of premalignant lesions, an attractive treatment option is to use chemoprevention to stop the initiation and progression of early stage (stage 1 or 2) oral cavity cancer. This Research Project is designed to examine the effects of chemopreventive agents on events associated with tumor initiation, promotion, and progression (xenobiotic metabolism, formation of adducts and reactive oxygen species, cyclin D1 and p16 gene expression, tumor growth factor beta receptor) and with molecular events associated with the transformation of normal oral mucosa cells to the premalignant and malignant stages. The laboratory aspects identified by their studies, whereas the design and strategy for application of chemopreventative agents will be under the direction of Drs. Stoner and Schuller in this Research Project 5. The chemopreventative agents selected for study will be study to interface with specific mechanisms/gene expressions associated with oral cancer development that are identified by these research projects. Data from each project on the cellular and molecular parameters involved in malignant development and progression will be used to guide the studies in Project 5, i.e., selection of candidate genes will be based on their ability to inhibit to inhibit particular stages of the carcinogenic process. The chemopreventative studies will be organized into three Specific Aims: Aim 1. Evaluate ability of chemopreventative agents to inhibit cell metabolism, DNA adduct formation, and generation of oxidants of/by TACs. This Specific Aim will be performed in collaboration with Research Project 1, who will perform the chemopreventative studies as directed by Research project 5. Aim 2. Evaluate the ability of chemopreventative agents to inhibit or modulate the expression of cell cycle regulatory genes. This Specific Aim will done in collaboration with Research Projects 2 and 3, who will perform studies to determine the effect of chemopreventative agents on the modulation/inhibition of cell cycle regulatory gene expression. Aim 3. Determine the ability of chemopreventative agents to inhibit the TAC transformation of normal oral mucosal cells to premalignant cells and the conversion of premalignant cells to malignancy by TACs. This Specific Aim will bone in collaboration with Research Project 4. Chemopreventative agents will be selected by Research Project 5 that are designed to inhibit the TAC transformation or normal oral mucosa cells and inhibit the malignant conversion of premalignant cells by TACs.